For decades, researchers primarily focused on signaling mechanisms involving secreted molecules that diffuse through the extracellular space to reach neighboring cells. Recent scientific understanding, however, has revealed a specialized and highly direct method of communication carried out by delicate, hair-like cellular protrusions called cytonemes. These dynamic structures act as dedicated conduits, allowing cells to establish precise, long-distance communication links across tissues.
What Are Cytonemes?
Cytonemes are thin, tubular extensions of the cell membrane that serve as specialized messengers for biological signaling. They are a specific type of filopodium, which is a general term for finger-like plasma membrane projections featuring a core bundle of tightly packed actin filaments that provide structural support and facilitate movement.
These projections are remarkably slender, typically measuring between 100 and 500 nanometers in diameter. Despite their fragility, they can extend over astonishing distances, often spanning many cell diameters, with some examples recorded at lengths exceeding 150 micrometers. Cytonemes are highly dynamic, constantly extending and retracting in a search-and-capture mechanism, helping them locate and connect with specific target cells.
Unlike general filopodia, which are often involved in cell motility or sensing the environment, cytonemes are specifically dedicated to the exchange of signaling molecules. They create a physical bridge that bypasses the need for signals to passively diffuse through the surrounding tissue fluid, ensuring that communication is both rapid and highly directed between non-adjacent cells.
The presence of the cytoskeletal element actin within their core is what drives the rapid formation and movement of the cytoneme structure. Proteins like Diaphanous and SCAR, which help assemble and organize actin filaments, are required for cytoneme extension. This internal machinery allows the cell to actively manage the length and direction of the projection to seek out its signaling partner.
The Mechanism of Signaling Transfer
Cytonemes facilitate intercellular communication primarily through a direct delivery system, acting like a cellular pipeline for signaling molecules. This mechanism centers on the formation of a transient, direct contact between the cytoneme tip of one cell and the membrane of a target cell, a junction referred to as a “morphogenetic synapse.”
One of the main modes of transfer involves the movement of signaling molecules, known as ligands or morphogens, from the source cell to the target cell along the cytoneme membrane. These morphogens, which include proteins like Hedgehog (Hh), Decapentaplegic (Dpp), and Wnt, are often embedded within the cytoneme’s membrane or transported in vesicles that travel along the projection. Once the cytoneme tip makes contact with the receiving cell, the morphogen is transferred directly to the target cell’s surface receptors.
A second mechanism involves the cytoneme carrying the receptor for a particular signal, rather than the signal itself. In this scenario, the receptor-bearing cytoneme extends from the receiving cell toward the signal-producing cell to physically “capture” the ligand at its source. For instance, the Dpp receptor Thickvein (Tkv) can be found in puncta moving along cytonemes that extend toward Dpp-producing cells.
By physically linking the cells, cytonemes are instrumental in establishing and maintaining morphogen gradients. These gradients are patterns of concentration across a tissue that instruct cells to adopt different fates. The concentration of the signal received is directly related to the stability and frequency of cytoneme contact, providing a mechanism for spatial precision in development.
Roles in Tissue Development and Repair
In the developing embryo, cytonemes ensure that cells receive the correct positional information to differentiate into the right cell type at the right time. They are crucial for processes that require coordination over long distances, such as the formation of limbs and organs.
A classic example comes from the Drosophila wing disc, a model for organ development, where cytonemes regulate the distribution of the morphogens Dpp and Hedgehog. Cytonemes extend from receiving cells toward the source of Dpp, forming a gradient that precisely dictates the size and shape of the developing wing. This targeted delivery ensures that each cell receives a specific concentration of the signal necessary for its differentiation.
In vertebrate development, cytonemes have been identified as the means for transporting the Sonic Hedgehog (Shh) signal in the chick limb bud, a process essential for establishing the anterior-posterior axis of the limb. Furthermore, during the development of the nervous system in mammals, cytonemes mediate the transfer of Shh to establish proper neural tube patterning. Compromised cytoneme function in these systems leads to significant developmental defects, underscoring their importance.
Beyond embryonic development, these structures also play a role in maintaining adult tissues and coordinating repair following injury. They help manage tissue homeostasis by regulating signals that control cell proliferation and differentiation. For example, cytonemes are involved in coordinating cell migration and growth factor signaling during wound closure and tissue regeneration, ensuring the organized restoration of damaged areas.
Cytonemes and Disease Progression
The precision and efficiency of cytoneme-mediated signaling, while beneficial in development, can be exploited by diseased cells, particularly in the context of cancer. Cancer cells often hijack these communication structures to promote their own growth and survival. Cytonemes can form between neoplastic cells and their surrounding tumor microenvironment, facilitating the exchange of growth factors and other pro-survival signals.
Research using models of Drosophila tumors, such as those involving the Epidermal Growth Factor Receptor (EGFR) and RET oncogenes, has demonstrated that cytoneme formation is necessary for the tumors to receive the signals they need to grow. In these models, genetically impairing the ability of cells to form cytonemes effectively suppresses tumor progression and increases organism survival. This suggests that the structures are actively required for malignancy.
Cytonemes also appear to be involved in glioblastoma, a severe brain cancer, where they are described as ultralong membrane protrusions called tumor microtubes. These structures allow tumor cells to communicate with one another, promoting invasion, proliferation, and resistance to radiation and chemotherapy. By creating these physical connections, cancer cells can efficiently share resources or signals that help them overcome therapeutic challenges.
The involvement of cytonemes in tumor-stroma communication highlights their potential as therapeutic targets. Blocking the formation or function of these signaling bridges could disrupt the dialogue between tumor cells and their supportive environment, effectively starving the cancer of necessary growth signals.